The primary determinants of intracellular sickle hemoglobin polymer formation in sickle erythrocytes is hemoglobin concentration and composition. Measurements of polymer formation in SS, AS and SC erthrocytes were used to demonstrate that polymer formation which decreases with increasing oxygen saturation can be quantitatively determined by experimental measurement and by thermodynamic analysis. Polymer formation in the sickle syndromes can account for 80% of the variation in hemolytic anemia and general clinical severity. In alpha-thalas-semia, the improvement in red cell survival and hemolytic anemia is consistent with the reduction in the potential for polymer formation. The reduced MCHC observed in alpha-thalassemia coexisting with sickle cell disease is a direct consequence of the overall reduction in erythrocyte density, erythrocyte heterogeneity and the proportion of dense cells. The biophysical and biochemical understanding of sickle cell anemia has provided a rationale for a number of therapeutic approaches. For example, deoxyhemoglobin S polymerization is sterio-specifically inhibited by dipeptides. These studies are continuing with x-ray crystallographic analysis to determine the precise binding site of these compounds. Finally, we have begun to examine the factors which determine extent and type of globin chain production using the human continuous cell line, K562 which is inducible for hemoglobin production.